trombosi i cÀncerpancreas 123 dalteparin control 12 % 31 % 3 % 3 % nd protecht 2009 adv / met solid...
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TROMBOSI I CÀNCER
Dra. Carme Font
Especialista en Medicina Interna
Servei d’Oncologia Mèdica
Hospital Clínic de Barcelona
Juny 2016
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Hipercoagulabilitat i càncer. Síndrome de Trousseau.
• 1865: Tromboflebitis migratòria i neoplàsia oculta visceral.
• Síndrome de Trousseau:
- Tromboembolisme venós. - Tromboembolisme arterial.
- Endocarditis trombòtica no bacteriana.
- Microangiopatia trombòtica.
- Coagulació intravascular disseminada. Varki A, Blood 2007
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Càncer –> Hipercoagulabiliat
Tríada de Virchow
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Inflamació – Hemostàsia –> Progressió Càncer
Intravasació
Extravasació
Transport
Evasió immune
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Prognosis of cancers associated with venous thromboembolism.
Sorensen HT. N Engl J Med 2000
Major mortalitat per l’event trombòtic?
Hipercoagulabilitat Agressivitat tumoral?
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ASCO Meeting 2016
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Heit JA et al. Arch Intern Med. 2002
Pacients amb càncer
20%
Total TVP - TEP
Tromboembolisme venós associat al càncer
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Trends in Cancer Statistics
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Trends in Cancer Statistics
CA: A Cancer Journal for Clinicians; Volume 64, Issue 1, pages 9-29, 7 JAN 2014 DOI: 10.3322/caac.21208
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Tromboprofilaxi primària en càncer
Khorana et al. Blood 2012
Retrospectiu N = 17,874 76% ambulatoris
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Tromboprofilaxi
primària en
pacients
ambulatoris
que reben
quimioteràpia?
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Trial Tumor n Treatment VTE Major
bleeding
Survival
FAMOUS
2004
Solid tumors 385 Dalteparin
Placebo
2.4 %
3.3 %
0.5%
0 %
P=0.03
SIDERAS
Adv / Met
Solis umors
141 Dalteparin
Control
6 %
7 %
3 %
7 %
ND
TOPIC-1 Metastatic
Breast
353 Certaparin
Placebo
4 %
4 %
1.7%
0 %
ND
TOPIC-2 Metastatic
Lung
547 Certoparin
Placebo
4.5 %
8.3 %
3.7 %
2.2 %
ND
PRODIGE Gliomas 186 Dalteparin
Placebo
11 %
17 %
5.1 %
1.2 %
ND
CONKO-004
2015
Adv / Met
Pancreas
312 Enoxaparin
Control
1.3 %
9.9 %
ND ND
UK FRAGEM
2009
Adv / Met
Pancreas
123 Dalteparin
Control
12 %
31 %
3 %
3 %
ND
PROTECHT
2009
Adv / Met
Solid tumors
1150 Nadroparina
Placebo
2 %
3.9 %
0.7 %
0 %
ND
SAVEONCO
2012
Adv / Met
Solid tumors
3212 Semuloparin
Placebo
1.2 %
3.4 %
1.2 %
1.1 %
ND
P<0.01
P=0.02
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Trial Tumor n Treatment VTE Major
bleeding
Survival
FAMOUS
2004
Solid tumors 385 Dalteparin
Placebo
2.4 %
3.3 %
0.5%
0 %
P=0.03
SIDERAS
Adv / Met
Solis umors
141 Dalteparin
Control
6 %
7 %
3 %
7 %
ND
TOPIC-1 Metastatic
Breast
353 Certaparin
Placebo
4 %
4 %
1.7%
0 %
ND
TOPIC-2 Metastatic
Lung
547 Certoparin
Placebo
4.5 %
8.3 %
3.7 %
2.2 %
ND
PRODIGE Gliomas 186 Dalteparin
Placebo
11 %
17 %
5.1 %
1.2 %
ND
CONKO-004
2015
Adv / Met
Pancreas
312 Enoxaparin
Control
1.3 %
9.9 %
ND ND
UK FRAGEM
2009
Adv / Met
Pancreas
123 Dalteparin
Control
12 %
31 %
3 %
3 %
ND
PROTECHT
2009
Adv / Met
Solid tumors
1150 Nadroparina
Placebo
2 %
3.9 %
0.7 %
0 %
ND
SAVEONCO
2012
Adv / Met
Solid tumors
3212 Semuloparin
Placebo
1.2 %
3.4 %
1.2 %
1.1 %
ND
P=0.02
P<0.001
NS
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PROTECHT Caldria tractar 53 pacients per evitar
un event trombòtic arterial o venós
SAVE-ONCO Caldria tractar 45 pacients per evitar un
event trombòtic venós NO diferències en mortalitat
¿Tromboprofilaxi primària en pacients
ambulatoris en QUIMIOTERÀPIA?
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N= 17,984
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Model Predictiu de risc d’MTV per pacients ambulatoris en tractament amb quimioteràpia
Khorana et al. Blood 2008
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Biomarcadors potencials
Ingrid Pabinger Cihan Ay Universitat de Viena
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4.2.1. In outpatients with cancer who have no additional risk factors for VTE, we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B)
and recommend against the prophylactic use of vitamin K antagonists (Grade 1B) . 4.2.2. In outpatients with solid tumors who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic dose LMWH or LDUH over no prophylaxis. 4.4. In outpatients with cancer and indwelling central venous catheters, we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and suggest against the prophylactic use of vitamin K antagonists (Grade 2C). Additional risk factors include: previous venous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide.
American College of Chest Physicians (ACCP) Guidelines 2012
Cancer outpatients thromboprophylaxis
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4.2.1. In outpatients with cancer who have no additional risk factors for VTE, we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B) .
4.2.2. In outpatients with solid tumors who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic dose LMWH or LDUH
over no prophylaxis. 4.4. In outpatients with cancer and indwelling central venous catheters, we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and suggest against the prophylactic use of vitamin K antagonists (Grade 2C). Additional risk factors include: previous venous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide.
American College of Chest Physicians (ACCP) Guidelines 2012
Cancer outpatients thromboprophylaxis
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Malaltia tromboembòlica venosa (MTV)
en el pacient oncològic • Incidència 4 - 20%
• 50% en autòpsies
• Segona causa de mort
• Morbilitat
Khorana AA, JTH 2007 Prandoni P, Blood 2002
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Risc hemorràgic
Lee AY, Blood 2013
• Controlar causa
- Corregir alteracions coagulació
- Embolizació arterial
- Cirurgia
- Radioteràpia hemostàtica
• Filtre de cava removible
- Contraindicació anticoagulació
• Sagnat tumoral
• Plaquetopènia per quimioteràpia / infiltració medul.lar
• Coagulopatia per disfunció hepàtica / malabsorció vit K
• Coagulació intravascular disseminada / Sepsis
• Anticoagulació
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Morbilitat associada a MTV en càncer:
21% risc anual de recorrència 12% risc anual d’hemorràgies majors
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CLOT Investigators
N Engl J Med 2003
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Trial Study drug
N Observation period
Recurrent VTE
Major bleeding
Survival
CLOT 2003
Dalteparin 25% dose reduction after 1 month
672 6 months 17% vs 9% P=0.02
4% vs 6% P=NS
41% vs 39% P= NS
CANTHANOX 2002
Enoxaparin Full dose once daily
146 3 months 21% vs 10% P=0.09
16% vs 7% P=0.09
23% vs 11% P=0.07
ONCENOX 2006
Enoxaparin 2 schemes full dose twice and once daily
122 6 months 10% vs 7% vs 6% p=NS
3% vs 6% vs 11% P=NS
32% vs 23% vs 42% P=NS
LITE 2006
Tinzaparin Full dose
200 3 months 16% vs 7% P=0.044
7% vs 7% P=NS
19% vs 20% P=NS
CATCH 2015
Tinzaparin Full dose
900 6 months 10% vs 7% P=0.07
1% vs 1% P=NS
34% vs 32% P=NS
Cancer-associated thrombosis treatment
Recorrència MTV
10-21% AVK vs. 7-10% HBPM
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1ª elecció HBPM: - Disminució 50% risc recorrència TEV
- Facilitat interrupcions temporals (puncions, plaquetopènia…)
- No interaccions farmacològiques warfarina
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Alternativa: anti vitK INR 2-3
- No accés HBPM
- Insuficiència renal FG <30 mL/min
- Hipersensibilitat a heparina
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In patients with DVT of the leg or PE and no cancer, as
long-term (first 3 months) anticoagulant therapy, we suggest:
Dabigatran
Rivaroxaban
Apixaban or
Edoxaban over VKA (Grade 2B).
For patients who are not treated with dabigatran, rivaroxaban,
apixaban or edoxaban, we suggest
VKA therapy over LMWH (Grade 2C).
ACCP Guidelines 2016
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Factors that may influence which anticoagulant is chosen. Factor Preferred anticoagulant Cancer LMWH
Pregnancy or pregnancy risk LMWH
Liver disease and coagulopathy LMWH
Renal disease FG <30ml/min AVK
Poor compliance AVK
Cost, coverage, licensing Varies among regions and individual circumstances
2016
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Nous anticoagulants
directes per
MTV associada al
càncer?
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RE-COVER I1 EINSTEIN DVT2 EINSTEIN PE3 AMPLIFY4 Hokusai-VTE5
Dabigatran Rivaroxaban Rivaroxaban Apixaban Edoxaban
Eficàcia
No inferior No inferior No inferior No inferior No inferior
Seguretat
Sagnat major + CRNM
Menor NS NS Menor Menor
Sagnat major NS NS Menor Menor NS
Sagnat CRNM NI NS NS Menor Menor
Cualsevol sagnat Menor NI NI NI Menor
Assajos clínics fase III en ETV: NOACs vs Warfarina
NI=no informado; NS=no significativo estadísticamente CRMN= no mayor clínicamente relevante.
1. RE-COVER: N Engl J Med 2009 2. EINSTEIN DVT; N Engl J Med 2010 3. EINSTEIN–PE N Engl J Med 2012 4. AMPLIFY: N Engl J Med 2013 5. Hokusai-VTE : N Engl J Med 2013
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RE-COVER1# Dabigatran
EINSTEIN DVT2
Rivaroxaban EINSTEIN PE3 Rivaroxaban
AMPLIFY4 Apixaban
Hokusai-VTE5 Edoxaban
Pacients, N 2539 3449 4832 5395 8292
Edat (anys) 55 56 58 57 56
Dones (%) 42 43 47 41 43
Aclarament de creatinina <50 mL/min (%)
NI 7 8 6 7
TVP (%) 69 99 - 65 59
EP±TVP (%) 31 0,6 100 35 40
Sense causa (%) NR 62 65 90 65
Càncer (%) 5 6 5 3 9†
TEV previ 26 19 19 16 18
NOACs vs Warfarina per TEV: característiques basals
1. RE-COVER: N Engl J Med 2009 2. EINSTEIN DVT; N Engl J Med 2010 3. EINSTEIN–PE N Engl J Med 2012 4. AMPLIFY: N Engl J Med 2013 5. Hokusai-VTE : N Engl J Med 2013
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Journal of Thrombosis and Haemostasis 2014
Five studies were included, with 19 060 patients,
of whom 973 (5.1%) had active cancer.
The pooled incidence rates of
Recurrent VTE were
4.1% (95% CI 2.6-6.0) with NOACs, and
6.1% (95% CI 4.1-8.5) with VKAs (RR 0.66, 95% CI 0.38-1.2).
Major or non-major clinically relevant bleeding were
15% (95% CI 12-18) with NOACs, and
16% (95% CI 9.9-22) with VKAs (RR 0.94, 95% CI 0.70-1.3).
Solid basis for a head-to-head comparison
of NOACs with LMWH in cancer patients.
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Datos de NAOD en pacientes con cáncer activo.
• Estudis no dissenyats per avaluar eficàcia i seguretat en càncer.
• NOACs vs AVK i NO comparat HBPM (tractament estàndar).
• No antídots.
• Interacció potencial amb quimioteràpia / hormonoteràpia /
antiangiogènics…
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Duració de tromboprofilaxi secundària?
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Hasta 2007
N=3805 pacientes con cáncer
N=1684 (44%) enfermedad metastásica
N=1464 (38%) < 3 meses cáncer
N=1643 (43%) tto prolongado HBPM
N=1855 (49%) tto prolongado AVK
N=146 (4%) filtro de cava
Periodo de seguimiento: 3 meses
90 pacientes recurrencia TEP (2.4%)
100 pacientes recurrencia TVP (2.6%)
40 (44%) fallecieron por TEP
156 (4.1%) hemorragia mayor
46 (29%) fallecieron
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Rodger MA 2008
Vienna 2010
DASH score 2012
Ottawa score 2012 derivation
Ottawa score 2012 validation
External validation 2013 Den Exter
N 646 929 1818 543 819 419
Cohort Prospective Prospective Meta-anaysis Retrospective derivative cohort
Pooled data CLOT + Canthanox
Predictive variables
Men: none Women: . Age > 60yr . PTS . BMI > 30 . D-dimer > 250 during anticoagulation
Gender Location first VTE D-dimer after anticoagulation
Male Age< 50 yr Hormonal therapy Abnormal D-dimer after anticoagulation
Female sex +1 Prior VTE +1 Lung cancer +1 Breast cancer -1 TNM 1 -2
Female sex +1 Prior VTE +1 Lung +1 Breast -1 TNM 1-2 -1
VTE recurrence Low risk
< 1 point 1.6% (95%CI 0.3%-4.6%)
< 180 points 4.4% (95%CI 2.7%-6.2%)
< 1 point 3.1% (95%CI 2.3-3.9)
< 0 LOW 4.5% > 1 HIGH 19%
< -1 LOW 5.1% 0 INTERMEDIATE
9.9% > 1 HIGH 15.8%
LOW 2.4% 8.8% INTERMEDIATE HIGH 15.9%
Models predictius per identificar a pacients amb
baix risc de recorrència de MTV
Kyrle PA Thromb Res 2014; Khorana AA Thromb Res 2016
Unable
to validate
2013
Ahn S et al.
N=546
LOW 13.2%
HIGH 22.4%
Unable
to validate
2015
Lee AY et al.
N=900
CATCH study
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Factors de risc de MTV
múltiples i canviants
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FACTOR A FAVOR EN CONTRA
Tumor Neoplàsia activa Remissió
Tractament Quimioteràpia -
Hormonoteràpia -
Eritropoyetina
Gravetat event Risc vital No risc vital
Sd posflebítica
Risc hemorràgic Baix Alt
Factors adicionals Obesitat Factors adicionals
Performance status en event inicial
Gènere femení com cirurgia …
Catèter venós central
Preferència pacient Evitar recorrència Evitar sagnat
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Moltes gràcies !